小柯机器人

TASL是与SLC15A4相关的接头蛋白
2020-05-15 23:56

奥地利科学院Giulio Superti-Furga、Manuele Rebsamen等研究人员合作发现,TASL是与SLC15A4相关的接头蛋白,可通过TLR7–9激活IRF5。该项研究成果于2020年5月13日在线发表在《自然》杂志上。

研究人员发现,由CXorf21(一种与系统性红斑狼疮相关的基因)编码未知的蛋白质与溶酶体转运蛋白SLC15A4相互作用,溶酶体转运蛋白SLC15A4也是內吞溶酶体Toll样受体(TLR)机器的重要组成部分,但与自身免疫性疾病也有关联。这种I型干扰素诱导型蛋白(被命名为“ TLR接头与溶酶体上的SLC15A4相互作用”蛋白,TASL)的丢失消除了原代和转化的人类免疫细胞中对溶酶体TLR激动剂的响应。SLC15A4或TASL的缺失会在不影响NF-κB和MAPK信号转导的情况下专门削弱IRF途径的激活,这表明配体识别和TLR参与了溶酶体的正常发生。TASL的突变表明,其定位和功能依赖于与SLC15A4的相互作用。TASL包含一个介导IRF5募集和激活的保守pLxIS基序(其中p表示亲水残基,x表示任何残基)。
 
这一发现表明TASL是TLR7、TLR8和TLR9信号转导的先天性免疫衔接分子,表明与IRF3衔接分子STING、MAVS和TRIF的明显相似性。TASL被鉴定为通过SLC15A4将溶酶体TLR连接至IRF5转录因子的成分,这一发现为这些蛋白参与系统性红斑狼疮提供了机制解释。
 
附:英文原文

Title: TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7–9

Author: Leonhard X. Heinz, JangEun Lee, Utkarsh Kapoor, Felix Kartnig, Vitaly Sedlyarov, Konstantinos Papakostas, Adrian Csar-Razquin, Patrick Essletzbichler, Ulrich Goldmann, Adrijana Stefanovic, Johannes W. Bigenzahn, Stefania Scorzoni, Mattia D. Pizzagalli, Ariel Bensimon, Andr C. Mller, F. James King, Jun Li, Enrico Girardi, M. Lamine Mbow, Charles E. Whitehurst, Manuele Rebsamen, Giulio Superti-Furga

Issue&Volume: 2020-05-13

Abstract: Toll-like receptors (TLRs) have a crucial role in the recognition of pathogens and initiation of immune responses1,2,3. Here we show that a previously uncharacterized protein encoded by CXorf21—a gene that is associated with systemic lupus erythematosus4,5—interacts with the endolysosomal transporter SLC15A4, an essential but poorly understood component of the endolysosomal TLR machinery also linked to autoimmune disease4,6,7,8,9. Loss of this type-I-interferon-inducible protein, which we refer to as ‘TLR adaptor interacting with SLC15A4 on the lysosome’ (TASL), abrogated responses to endolysosomal TLR agonists in both primary and transformed human immune cells. Deletion of SLC15A4 or TASL specifically impaired the activation of the IRF pathway without affecting NF-κB and MAPK signalling, which indicates that ligand recognition and TLR engagement in the endolysosome occurred normally. Extensive mutagenesis of TASL demonstrated that its localization and function relies on the interaction with SLC15A4. TASL contains a conserved pLxIS motif (in which p denotes a hydrophilic residue and x denotes any residue) that mediates the recruitment and activation of IRF5. This finding shows that TASL is an innate immune adaptor for TLR7, TLR8 and TLR9 signalling, revealing a clear mechanistic analogy with the IRF3 adaptors STING, MAVS and TRIF10,11. The identification of TASL as the component that links endolysosomal TLRs to the IRF5 transcription factor via SLC15A4 provides a mechanistic explanation for the involvement of these proteins in systemic lupus erythematosus12,13,14.

DOI: 10.1038/s41586-020-2282-0

Source: https://www.nature.com/articles/s41586-020-2282-0

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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